Erythrocyte Na+, K+ and Ca2+, Mg(2+)-ATPase activities in hypertensives on angiotensin-converting enzyme inhibitors.

OBJECTIVE: To investigate erythrocyte membrane Na+, K(+)- and Ca2+, Mg(2+)-ATPase activities in newly diagnosed hypertensive patients before and after 2, 4, and 6 months of treatment with enalapril or captopril as monotherapy. METHODS AND RESULTS: Na+, K(+)-ATPase activity (nmol ATP hydrolysed/min per mg protein) rose by 6 months of treatment in both groups when values were compared in each treated group over time (4.5 +/- 0.8 to 9.9 +/- 1.2; 4.9 +/- 0.8 to 10.5 +/- 1.7, respectively, p < 0.001 for both). When the treated groups were compared with controls at each period of time, Na+, K(+)-ATPase activity was higher at months 4 and 6 (p < 0.001) for both groups, respectively). Ca2+, Mg(2+)-ATPase activity (nmol ATP hydrolyzed/min per milligram protein) in the absence and in the presence of calmodulin increased in the enalapril (6.4 +/- 0.7 to 8.9 +/- 0.95, p < 0.05; 13.4 +/- 1.2 to 17.2 +/- 1.2, p < 0.05, respectively) and captopril (7.0 +/- 0.6 to 8.5 +/- 0.7; 14.4 +/- 1.1 to 16.0 +/- 1.0, p < 0.05, respectively) groups after 6 months of treatment compared within each treated group over time. When patient groups were compared with controls at time 0, 2, 4, and 6 months, the pump activity was higher in the treated groups at 6 months. CONCLUSION: The long-term enhancement of cell membrane Na+, K(+)-and Ca2+, Mg(2+)-ATPase activity associated with enalapril and captopril therapy may represent a specific effect of these agents or alternatively, a nonspecific outcome of blood pressure reduction.

Comparison of serum C-reactive protein concentrations for laparoscopic versus open cholecystectomy.

In an attempt to quantify the difference in tissue damage between open cholecystectomy (OC) and laparoscopic cholecystectomy (LC), we have compared in a prospective manner the pre- and post-operative concentrations of serum C-reactive protein (CRP) in 17 patients undergoing LC and 13 patients undergoing OC. In addition, we measured the pre- and postoperative white blood cell counts (WBC), the postoperative body temperature, and the postoperative duration of hospitalization. There were no differences in the preoperative serum CRP concentrations--5.9 +/- 2.62 mg/l (mean +/- SD) for the LC group and 6.12 +/- 2.38 mg/l for the OC group. Serum CRP rose markedly following OC compared to that of patients who underwent LC (128.6 +/- 45.1 mg/l vs 26.8 +/- 10.5 mg/l) (P < 0.001). There were also significant differences in the postoperative WBC count (14,000 +/- 2,900 cells for the OC group vs 10,600 +/- 3,000 cells for the LC group), the postoperative body temperature (37.5 +/- 0.3 degrees C vs 37.0 +/- 0.3 degrees C), and the postoperative hospital stay (5.5 +/- 1.5 days vs 1.9 +/- 0.9 days). There was no correlation between serum CRP concentrations and the other postoperative parameters. These results provide us with biochemical evidence supporting the clinical observation that LC is far less traumatic to the patient than OC.

Are elevated liver enzymes and bilirubin levels significant after laparoscopic cholecystectomy in the absence of bile duct injury?

OBJECTIVE: Increased aspartate aminotransferase (AST), alanine aminotransferase (ALT), and bilirubin levels were noted incidentally after a laparoscopic cholecystectomy. The percentage in which such elevation occurs and its clinical significance in the absence of bile duct injury were investigated. SUMMARY BACKGROUND DATA: Bile duct injury is the most feared complication of laparoscopic cholecystectomy. Some laboratory tests may be indicative of this complication, such as increases in liver enzyme (AST, ALT, and alkaline phosphatase [ALP]) and bilirubin. These parameters have not been investigated in patients who had laparoscopic cholecystectomy and in whom no damage to the bile duct was noted. METHODS: Sixty-seven patients with normal results of preoperative liver function test were entered into the study. Blood was collected 24 hours after laparoscopic cholecystectomy, and AST, ALT, ALP, and bilirubin levels were measured. RESULTS: A mean 1.8-fold increase in AST occurred in 73% of patients; 82% showed a 2.2-fold increase in ALT. A statistically nonsignificant increase was noted in 53% of patients (ALP remained within normal limits), and in 14% of patients bilirubin levels were increased (they were primarily of the unconjugated type). CONCLUSIONS: In many patients a significant increase in AST and ALT levels occurred after laparoscopic cholecystectomy, but they returned to normal values within 72 hours. The cause of this is unclear, and these elevations appear to have no clinical significance.

Reduced Na+, K(+)-ATPase activity in patients with pseudohypoaldosteronism.

Pseudohypoaldosteronism is a hereditary salt-wasting syndrome usually seen in infancy with weight loss, dehydration, and failure to thrive. The pathophysiologic origin of pseudohypoaldosteronism is unknown. The defect could be related to the unresponsiveness of target organs to mineralocorticoids resulting in hyponatremia, hyperkalemia, and markedly elevated plasma aldosterone and renin levels. Red blood cell Na+, K(+)-ATPase activity was measured in a pair of twins with pseudohypoaldosteronism, in an unrelated child with hypoaldosteronism, and in an age-matched group of 50 healthy infants and young children. The enzyme was assayed by a method that couples ATP hydrolysis with NADH oxidation. Plasma renin and aldosterone levels were measured by RIA. Red blood cell Na+, K(+)-ATPase activity in the twins with pseudohypoaldosteronism was very low at the time of diagnosis (3 wk). In both twins a time-related gradual increase in enzyme activity was observed during the 1st mo of life, reaching control values between 6 and 8 mo of age. This increase was associated with both a reduction in salt requirement and clinical improvement. Plasma renin activity and aldosterone levels were very high at the time of diagnosis. Plasma renin activity reverted gradually to normal values, whereas aldosterone levels remained high throughout the follow-up period. The child with hypoaldosteronism had normal Na+, K(+)-ATPase activity at diagnosis and during follow-up.

Renal uric acid handling in non-insulin-dependent diabetic patients with elevated glomerular filtration rates.

1. Hypouricaemia is prevalent in diabetic patients. In most of the studies, the diabetic patients had some degree of diabetic nephropathy as evidenced by a decreased glomerular filtration rate and proteinuria. Therefore we studied renal uric acid handling in a group of type II diabetic patients with elevated glomerular filtration rates. 2. Eighteen type II diabetic patients with normal kidney functions and elevated glomerular filtration rate and a group of 18 healthy, age- and weight-matched control subjects, were studied. Serum fructosamine, creatinine and uric acid levels were determined. Twenty-four hour urine collections were obtained, and microalbumin, glucose, creatinine and uric acid, were measured. 3. The creatinine clearance was higher and the serum uric acid concentration was lower in the diabetic patients (P < 0.05). The 24 h urinary uric acid excretion and filtered uric acid load were similar in both groups. However, the derived parameters of uric acid clearance and fractional excretion were significantly higher in the diabetic patients (P < 0.002 and P < 0.05, respectively). A negative correlation was apparent between serum fructosamine concentration and serum uric acid concentration (r = -0.76). A positive correlation was found between serum fructosamine concentration and fractional uric acid excretion (r = 0.64) and between serum fructosamine concentration and filtered uric acid load (r = 0.66). A positive correlation was found between creatinine clearance and 24 h uric acid excretion (r = 0.61) and between creatinine clearance and filtered uric acid load (r = 0.82).(ABSTRACT TRUNCATED AT 250 WORDS)

Inhibition of human red blood cell glutathione reductase by valproic acid.

Glutathione reductase (GR) one of the enzymes of the glutathione redox cycle, plays a salient role in maintaining appropriate cellular levels of reduced glutathione. The enzyme in human red blood cells is inhibited in vitro by the anticonvulsant drug valproic acid (VPA). The inhibition is dose-dependent, reversible, uncompetitive and does not depend on the redox state of the enzyme. VPA also inhibits red blood cell GR activity in children being treated with the drug. The level of serum VPA correlates significantly with the suppression of GR activity.

Developmental toxicity of valproic acid.

Valproic acid is a very effective anticonvulsant agent widely used in the management of various forms of epilepsy. Administration of the drug during pregnancy results in increased incidence of congenital abnormalities in both humans and experimental animals. In recent years, a significant number of research efforts have attempted to define the contributory role of valproic acid to the impairment of normal prenatal growth and development. The present report summarizes current knowledge that has emerged from clinical and research studies. The specific topics include: the placental transfer of valproic acid; the teratogenic potential; structure-teratogenicity and dose-response relationships; species and strain differences; biochemical changes evoked by the drug in the fetus.

Early changes in hepatic redox homeostasis following treatment with a single dose of valproic acid.

Changes in reduced glutathione (GSH) and pyridine nucleotide phosphate levels as well as in the activities of the glutathione peroxidase-reductase system and glucose-6-phosphate dehydrogenase have been studied in rats after a single i.p. administration of various doses of valproic acid (VPA). GSH level decreased in a dose-dependent relation. At the end of 180 min GSH levels either returned to control limits (lower doses) or showed a tendency to normalize (higher doses). GSH loss was paralleled by the reduction in glutathione reductase activity. A significant NADPH reduction was also seen after animal exposure to high VPA doses. At the end of 180 min a maximal NADPH decrease was reached. The activities of both glutathione peroxidase and glucose-6-phosphate dehydrogenase were suppressed irrespective of whether animals were given low or high VPA doses.

Neurophysiological and biochemical changes evoked by valproic acid in the central nervous system.

(1) Valproic acid is an anticonvulsant agent widely used in the management of various forms of epilepsy, including absence, myoclonic and tonic-clonic seizures. (2) It also has anticonvulsant potency in a wide variety of animal models of epilepsy. (3) This action is generally thought to be exerted through modulation of the activity of the endogenous inhibitory neurotransmitter, gamma-aminobutyric acid. (4) Evidence that valproic acid interacts with the gamma-aminobutyric acid system is presented. (5) Interactions of valproic acid with other neurotransmitters, i.e. aspartate, glutamate, taurine, serotonin, as well as with cyclic nucleotides and hormones are also considered. (6) Direct effects of valproic acid on excitable membranes and its relationships with analgesia are outlined.

Heavy- and free light-chain myeloma associated with peripheral polyneuropathy.

Peripheral polyneuropathy, a rare complication of multiple myeloma, is generally associated with heavy-chain M-proteins and, in very rare instances, with free light-chain myeloma proteins. Here we describe a case of multiple myeloma and polyneuropathy with both monoclonal IgG and free lambda light chains in the blood. The patient also had free lambda light chains in the cerebrospinal fluid and urine.

Valproic acid and the liver.

Valproic acid (VPA) is widely used as an anticonvulsant, but therapy with the drug has been associated with hepatotoxicity, either reversible hepatic dysfunction or irreversible hepatic failure. Both clinical and experimental studies have revealed several VPA-related biochemical abnormalities in the liver: inhibition of the beta-oxidation and synthesis of fatty acids and inhibition of gluconeogenesis, urea synthesis, oxidative phosphorylation, and the glycine cleavage system. Other abnormalities noted include alteration in the protein conformation of the internal mitochondrial membrane, hyperammonemia, and increased bile flow. The mechanisms of such hepatotoxicity, whether mediated by VPA or by its metabolites, are still little understood. Susceptibility to VPA hepatotoxicity may be enhanced by such conditions as starvation, inborn errors of metabolism, additional neurological disease, and concomitant administration of enzyme-inducing drugs.

Induction of gamma-glutamyl transferase by dexamethasone in cultured fetal rat hepatocytes.

Hepatocytes isolated as a relatively pure population from normal fetal rats were maintained in primary monolayer culture for 4-10 days. Hepatocytes exhibited a small increase in basal gamma-glutamyl transferase (GGT) activity over time. Exposure to dexamethasone (10(-6) mol/l) elicited a rise in GGT activity after a lag of 24 h. The presence of the steroid was necessary to maintain induction, and its removal resulted in reversal of induction. The maximal response was 2- to 3-fold, 72 h after exposure to the steroid. After this maximal response, a gradual decay in enzyme activity occurred, despite the continuous presence of the hormone. Actinomycin D or cycloheximide given prior to/or simultaneously with the steroid prevented the induction, thus suggesting that both RNA and protein biosynthesis are necessary for induction to occur.

Liver damage induced by Oriental hornet venom sac extract at the level of subcellular fractions.

The hepatotoxic effect of venom sac extract (VSE) of the Oriental hornet has already been demonstrated using the well-known models of experimental toxicology: in vivo, isolated in situ and in vitro. The present work deals with a series of 48 rats treated daily with 5 mg VSE/kg body weight for 1-14 days. Serum activities of alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), and gamma-glutamyl transferase (GGT) were measured. Liver tissue fractionation was performed. Detailed information on the topographical and functional aspects of some enzyme changes was obtained in respect to the number of envenomations. The biochemical alterations are partially reversible. The biochemically proven liver damage induced by VSE correlated well with previous electron microscopic observations of damage to mitochondria and cell membranes.

Hepatotoxicity of hornet's venom sac extract in isolated perfused rat liver.

The changes in the activity of some enzymes in parenchymal liver cells were measured in the perfusate of rat isolated liver after a single envenomation with two different doses of Hornet's (Vespa orientalis) venom sac extract (VSE). The maximal observed enzymatic changes were significant: twenty four fold rise of alkaline phosphatase E.C.3.1.3.1(ALP), six fold rise of alanine aminotransferase E.C.2.6.1.2. (ALT) and nine fold rise of aspartate aminotransferase E.C.2.6.1.1. (AST) activity. There were moderate changes (four fold) in lactic dehydrogenase activity E.C.1.1.1.2.7. (LDH) and a non-significant change in gamma-glutamyl-transferase E.C.2.3.2.1. (GGT) activity. These changes varied with the venom's dose. Also a decrease in the rate of effluent draining out via the hepatic vein was noted as an additional sign of liver damage. In light of the biochemical evidence presented here, as well as in previous work, it seems that no further biochemical proof is needed to establish the hepatotoxicity of VSE in rats, cats and probably humans too. It seems that VSE is a predictable hepatotoxin causing a pattern of enzyme changes of the cholangiocellular type.

Effect of sodium valproate on subcellular fraction enzymes in rat liver.

Previous observations that valproic acid (VPA) causes hepatic damage prompted us to investigate the effect of large doses of the drug (0.6, 1.2 and 1.8 mmol/kg/day) on a number of liver enzymes located on different subcellular fractions. In mitochondria, glutamate dehydrogenase, aspartate aminotransferase and ornithine carbamoyltransferase were significantly increased (1.8 mmol/kg/day). In microsomes, gamma-glutamyltransferase activity increased significantly (1.8 mmol/kg) and cytochrome P-450 content decreased significantly (1.2 and 1.8 mmol/kg). In cytosol, both aspartate and alanine aminotransferase activities were increased at all dose levels. These results indicate that VPA induces dose-dependent changes in some liver enzyme activities.

Hepatotoxicity of hornet's venom sac extract, after repeated in vivo and in vitro envenomation.

The activity of some enzymes involved in hepatic function was measured in rats, in vivo, after one week's repeated envenomation with Hornet's (Vespa orientalis) venom sac extract (VSE) and in vitro in monolayers of tissue culture of rat hepatocytes treated with VSE. The maximal serum enzymatic changes observed in vivo were significant: twenty fold rise of alkaline phosphatase (ALP), a 7-8 fold rise of aspartate aminotransferase (AST) and a 4-5 fold rise in alanine aminotransferase (ALP) activity. Also 2-3x increases of both serum lactic dehydrogenase (LDH) and creatine phosphokinase (CPK) were noted. The maximal in vitro changes were observed after six days of daily envenomation. There were five fold rises of the activity of AST in the medium, as well as of two-three fold rises of ALT, ALP and LDH. These changes suggest that Hornet's VSE induces enzymatic changes in the liver after prolonged, repeated exposures. They also exclude a general effect, like shock, that might possibly occur in the intact animal, as the cause of the demonstrated hepatic damage.

Comparison of serum theophylline levels in asthmatic children receiving sustained-release and rapid-release theophylline tablets.

Serum theophylline levels were compared after the administration of a sustained-release (Theo-Dur, Key Pharmaceuticals, USA) vs. a rapid-release (Glyphyllin, Ikapharm, Israel) theophylline preparation to 24 children suffering from chronic bronchial asthma. They received each of the two drugs for a 5-d period, and serum theophylline levels were determined on the 6th d. Therapeutic serum levels were achieved in 66.6 and 75% of the patients receiving sustained-release and rapid-release theophylline preparations, respectively. The peak-trough difference for the rapid-release drug was higher than that of the sustained-release preparations (5.5 +/- 2.6 micrograms/ml vs. 2.6 +/- 2.3 micrograms/ml). Both drugs caused nearly the same low percentage of side effects (15 and 16.6%). A noncompliance rate of 16.6% was found with the rapid-release drug, and all the parents preferred the sustained-release drug is preferable for chronic treatment of children with bronchial asthma, as it maintains more stable serum theophylline levels and has a higher compliance rate.